Declining lung function is a consequence of aging that results from the gradual loss of alveoli. This debilitating process is exacerbated in the context of lung diseases that are oftentimes progressive and fatal. Recent data suggest that adult humans are capable of generating new lung tissue in response to a surgical reduction in lung volume. This raises the exciting possibility that, given the right cues, endogenous progenitor cells could be capable of restoring normal alveolar architecture and function in diseased lungs. The objective of this project is to identify epithelial stem cells in the adult lun that have the capacity to generate new alveolar tissue and the microenvironmental cues that trigger this response. Several obstacles have impeded previous efforts to identify human alveolar stem cells. These include the inability to perform interventional, longitudinal injury/repir studies in humans, striking dissimilarities between the lungs of humans and most model organisms, and a paucity of discriminating markers for putative progenitor cell populations. Here, the advantages of two model systems will be exploited to address these issues. In Specific Aim 1, the genetically tractable mouse will be used to identify, at the single cell level, cells with the ability to generate new alveolar epithelium. Because the lungs of rhesus macaques are more similar at the cellular level to those of humans than most model organisms, the mechanisms identified through functional studies in mice will be validated with data from pneumonectomized macaques. In Specific Aim 2, genetic loss of function experiments will be used to test the hypothesis that Notch, provided by the local fibroblast component of the regenerative niche, is critical for the generation of new alveolar epithelium in adults. In Specifi Aim 3, genetic loss of function and bone marrow transplants in mice will be used to test the hypothesis that AEC2 recruit monocytes to the lung post-PNX through the secretion of Ccl2. In the lung, IL13 polarizes these cells toward a wound healing M2 phenotype to promote adult alveologenesis. Together, this comprehensive, multi-organismal approach will address knowledge gaps surrounding the mechanisms of lung regeneration in adults. These data will provide novel cellular and molecular targets that can be leveraged to prevent or reverse the decline in lung function associated with the destruction of alveoli.